Many patients in the United States undergo mitral valve (MV) repair each year. Long-term studies have shown less optimistic results for repair durability. This brings into question the effectiveness of such surgical practice and suggesting that MV repair techniques can be improved upon. In most cases, failures were a result of disruption at the leaflet, chordae, or annular suture lines. These failure modes suggest excessive tissue stress and the resulting tissue damage as an etiologic factor. A fundamental aspect underling all types of MV repair is the relation between leaflet geometry, structure, and local tissue stress/homeostasis. Altered MV stress, caused by disorders such as tachycardia-induced cardiomyopathy, mitral regurgitation, and abnormal ventricular wall motion has been shown to induce significant changes in mitral valve interstitial cell (MVIC) activities and MV extracellular matrix (ECM) collagen content. Similarly, by changing the mechanical loading on the leaflet tissue, MV repairs may alter the MVIC deformation, ECM collagen content, and tissue homeostasis, and subsequently could limit durability of the repair. Therefore, understanding the repair-induced changes in the tissue stress and microstructure is quintessential in investigating the MV cellular activities and ultimately etiology of MV repair failure. Finite-element (FE) modeling has been employed to estimate native MV leaflet stress. Although important as first steps, these studies have not captured the complexity of MV geometry, microstructure, and mechanobiological responses to altered loading. Our long-term goal of the research program is elucidating the etiology of MV repair failure and studying how changes in leaflet tissue stress affect MVIC biosynthetic abilities, and how these changes in-turn affect MV repair durability. In the current project, we emphasize the repair-induced MV stress alteration and the changes in the microstructure of the MV tissues using a novel FE model. This model will allow us to directly connect MVIC deformation to altered loading during MV repair. We hypothesize that: MV mechanical loading controls tissue homeostasis and ECM remodeling (via MVICs), with deleterious repair-induced altered loading leading to microstructural changes that affect long-term repair durability. We propose the following specific aims: Specific Aim 1. Develop an anatomically faithful micro/meso-scale quasi-static 3D FE model of MV apparatus to quantify stress and deformation at cellular, tissue, and organ levels. Specific Aim 2 Assess the validity of FE model predictions by comparing the simulation results to in- vivo experimental data. Specific Aim 3 Investigate changes in regional tissue stress, microstructure, and MVIC deformation following repair.